Common variable immunodeficiency (CVID), which is the most common primary immunodeficiency disease, is a heterogeneous group of diseases characterized by defective immunoglobulin production that leads to recurrent infections and is complicated by an increased risk of autoimmune and malignant diseases. CVID results in a marked reduction in serum immunoglobulins, which are soluble proteins found in blood and other bodily fluids, and are one of the main defense mechanisms against infectious agents. The genetic causes of CVID have long been sought, but traditional genetic approaches have been only partially successful. Screening of genes known to be required for B-cell development and immunoglobulin production has led to the discovery of ten genes in which mutations can lead to CVID, but the genetic cause of the immune deficiency remains unknown in the overwhelming majority of patients (>80%). Ninety percent of patients with CVID present as simplex cases, while the remaining are familial cases. Genetic diagnosis in single individuals using sequencing of whole genomes or the complete coding regions (i.e., exomes) is now possible. Whole exome sequencing provides an efficient strategy to discover the genes for genetic disorders of unknown cause in small families and even in single individuals, not amenable to traditional genetic approaches. Therefore we plan to study 20 simplex CVID patients and their parents, seen at the University of Utah Clinical Immunology/Immunodeficiency Clinic, in whom other known genetic causes of CVID have been ruled out.